PMID- 32236425 OWN - NLM STAT- MEDLINE DCOM- 20210428 LR - 20211204 IS - 1523-5866 (Electronic) IS - 1522-8517 (Print) IS - 1522-8517 (Linking) VI - 22 IP - 10 DP - 2020 Oct 14 TI - A phase II study of continuous oral mTOR inhibitor everolimus for recurrent, radiographic-progressive neurofibromatosis type 1-associated pediatric low-grade glioma: a Neurofibromatosis Clinical Trials Consortium study. PG - 1527-1535 LID - 10.1093/neuonc/noaa071 [doi] AB - BACKGROUND: Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. METHODS: Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. RESULTS: Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. CONCLUSION: Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Ullrich, Nicole J AU - Ullrich NJ AD - Department of Neurology, Boston Children's Hospital, Boston, Massachusetts. AD - Dana-Farber/Boston Children's Cancer and Blood Disorders, Dana-Farber Cancer Institution, Boston, Massachusetts. FAU - Prabhu, Sanjay P AU - Prabhu SP AD - Departments of Radiology, Boston Children's Hospital, Boston, Massachusetts. FAU - Reddy, Alyssa T AU - Reddy AT AD - Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, California. FAU - Fisher, Michael J AU - Fisher MJ AD - Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - Packer, Roger AU - Packer R AD - Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, DC. FAU - Goldman, Stewart AU - Goldman S AD - Ann and Robert Lurie Children's Hospital, Chicago, Illinois. FAU - Robison, Nathan J AU - Robison NJ AD - Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California. FAU - Gutmann, David H AU - Gutmann DH AD - Department of Neurology, Washington University School of Medicine, St Louis, Missouri. FAU - Viskochil, David H AU - Viskochil DH AD - Department of Genetics, University of Utah, Salt Lake City, Utah. FAU - Allen, Jeffrey C AU - Allen JC AD - Departments of Pediatrics and Neurology, NYU Cancer Institute, NYU Langone Medical Center, New York, New York. FAU - Korf, Bruce AU - Korf B AD - Department of Genetics, University of Utah, Salt Lake City, Utah. AD - Department of Medical Genetics, University of Alabama, Birmingham, Alabama. FAU - Cantor, Alan AU - Cantor A AD - Department of Preventative Medicine, University of Alabama, Birmingham, Alabama. AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. FAU - Cutter, Gary AU - Cutter G AD - School of Public Health, University of Alabama, Birmingham, Alabama. AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. FAU - Thomas, Coretta AU - Thomas C AD - School of Public Health, University of Alabama, Birmingham, Alabama. AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. FAU - Perentesis, John P AU - Perentesis JP AD - Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. FAU - Mizuno, Tomoyuki AU - Mizuno T AD - Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. FAU - Vinks, Alexander A AU - Vinks AA AD - Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. FAU - Manley, Peter E AU - Manley PE AD - Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts. AD - Dana-Farber/Boston Children's Cancer and Blood Disorders, Dana-Farber Cancer Institution, Boston, Massachusetts. FAU - Chi, Susan N AU - Chi SN AD - Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts. AD - Dana-Farber/Boston Children's Cancer and Blood Disorders, Dana-Farber Cancer Institution, Boston, Massachusetts. FAU - Kieran, Mark W AU - Kieran MW AD - Department of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts. AD - Dana-Farber/Boston Children's Cancer and Blood Disorders, Dana-Farber Cancer Institution, Boston, Massachusetts. LA - eng GR - W81XWH-05-1-0615/Department of Defense Neurofibromatosis Research Program/International GR - UL1 TR002538/TR/NCATS NIH HHS/United States GR - P50 CA165962/CA/NCI NIH HHS/United States GR - U54 HD090255/HD/NICHD NIH HHS/United States GR - UL1 TR001855/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Neuro Oncol JT - Neuro-oncology JID - 100887420 RN - 0 (Antineoplastic Agents) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM CIN - Neuro Oncol. 2020 Oct 14;22(10):1415-1416. PMID: 32974639 MH - *Antineoplastic Agents/therapeutic use MH - Child MH - Everolimus/therapeutic use MH - *Glioma/diagnostic imaging/drug therapy MH - Humans MH - *Neurofibromatosis 1/drug therapy MH - Sirolimus/therapeutic use MH - TOR Serine-Threonine Kinases PMC - PMC7566451 OTO - NOTNLM OT - NF1 OT - PIK3K/mTOR pathway OT - RAD001 OT - everolimus OT - low-grade glioma OT - neurofibromatosis EDAT- 2020/04/03 06:00 MHDA- 2021/04/29 06:00 PMCR- 2021/04/01 CRDT- 2020/04/03 06:00 PHST- 2020/04/03 06:00 [pubmed] PHST- 2021/04/29 06:00 [medline] PHST- 2020/04/03 06:00 [entrez] PHST- 2021/04/01 00:00 [pmc-release] AID - 5814308 [pii] AID - noaa071 [pii] AID - 10.1093/neuonc/noaa071 [doi] PST - ppublish SO - Neuro Oncol. 2020 Oct 14;22(10):1527-1535. doi: 10.1093/neuonc/noaa071.